Nephropathy, for which no specific medicine is available, requires an artificial dialysis treatment in an advanced stage even though this treatment inflicts pain on patients. In particular, diabetic neuropathy has become a serious problem as the number of patients with diabetes has increased.
With regards to mechanisms of onset of diabetes, it is well known that severe insulin dysfunction induces a diabetic condition. Recently, one of the mechanisms for insulin dysfunction has been elucidated (Inada A. et al., Bunshi Tonyobyogaku [Molecular Diabetology] 10:73-81, 1999), and elucidation of the onset mechanism of and studies on the treatment of diabetes have been actively performed. However, for mechanisms of onset diabetic complications involving diabetic nephropathy, diabetic retinopathy and diabetic mental disorder, there is no effective and established diagnostic or therapeutic management.
Meanwhile, to develop diagnostic or therapeutic management of diabetes or diabetic complications, vigorous effort has made to establish optimal animal models. (JP 04-248941 A). However, animal model so far exhibits only hyperglycemia with low insulin but not diabetic complications identical to that of human. It has been reported that only a double transgenic (Tg) mouse obtained by crossing two gene-modified Tg mice exhibits diabetic nephropathy (J. Clinical Investigation, Vol. 108, No. 2, p. 261, 2001). However, in this double Tg mouse model, to develop diabetes and to maintain hyperglycemia, it is required to cross a Tg mouse that specifically overexpress inducible Nitric Oxide (iNOS) in insulin-producing β cells (J. Biol. Chem., Vol. 273, pp.2493-2496, 1998) with a Tg mouse overexpressing receptor for advanced glycosylation endproduct (RAGE) in vascular cells. High proteinuria and glomerulosclerosis which are similar to human diabetic nephropathy appear only when both transgenes are simultaneously expressed. In addition, modified overexpressions of iNOS in pancreatic β cells and RAGE in vascular cells are unusual situation. Thus, this model is artificial and far from actual diabetic condition, and no single animal model develops renal changes identical to those seen in humans.
It has been known that ICER suppresses insulin (A. Inada et al JBC 1999 vol. 274 no. 30 p. 21095-21103; A. Inada et al BBRC 1998 vol. 253 no. 3 p. 712-718) gene transcription, and that ICER is increased in the diabetic condition (Inada A. et al BBRC 1998 vol. 253 no. 3 p. 712-718), but no association of ICER with diabetic nephropathy has been known.
Thus, the development of a medicine effective for the diagnosis or the treatment of nephropathy including diabetic nephropathy and the development of a useful experimental system as a pathogenic model of nephropathy or diabetic nephropathy have been highly required.
The present invention mainly intends to provide a method useful for the diagnosis and the treatment of nephropathy including diabetic nephropathy and a transgenic non-human mammalian animal useful as a pathogenic model of diabetic nephropathy.